Tissue adhesives have many potential medical applications, including topical wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups, which are capable of reacting with the nucleophilic groups of the first component, to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al., in copending and commonly owned U.S. patent application Ser. No. 11/244,756 (U.S. Patent Application Publication No. 2006/0078536), describe polymer tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. The adhesives described in that disclosure overcome many of the limitations of hydrogel adhesives; however, the hydrogels are very fast curing so that they may not be optimal for some applications.
Arthur, in copending and commonly owned U.S. patent application Ser. No. 11/244,758 (U.S. Patent Application Publication No. 2006/0079599), describes polymer tissue adhesives formed by reacting poly(hydroxylic) compounds derivatized with acetoacetate groups and/or polyamino compounds derivatized with acetoacetamide groups with an amino-functional crosslinking compound. The adhesives described in that disclosure also overcome many of the limitations of hydrogel adhesives; however, the high concentrations of polyamines used may not be biocompatible to some tissues.
Futami et al. in U.S. Pat. No. 5,203,914 describe a dental impression composition which contains acetoacetylated polyvinyl alcohol, an aldehyde group-containing gelling agent, such as dialdehyde starch, and a filler, such as silica, alumina, and titanium oxide. A polymer tissue adhesive formed by reacting an oxidized polysaccharide with a poly(hydroxylic) compound derivatized with acetoacetate groups is not described in that disclosure.
Therefore, the problem to be solved is to provide a biocompatible tissue adhesive material having good adhesion to biological tissue, good cohesion, good mechanical strength, good aqueous and air stability, and a cure time that can be readily tailored to meet the needs of various applications.
Applicants have addressed the stated problem by discovering a polymer tissue adhesive formed by reacting an oxidized polysaccharide with a poly(hydroxylic) compound derivatized with acetoacetate groups in the presence of a base catalyst. The resulting adhesive has many desirable characteristics as a tissue adhesive and has a cure time that can be broadly controlled by adjusting the concentration of the base catalyst or by selecting base catalysts having different base strengths. Additionally, the adhesive is nontoxic to cells and non-inflammatory to tissue.